Yoshiko Matsuda

Gastric and intestinal claudin expression at the invasive front of gastric carcinoma

Like gastric and intestinal mucins, the tight junction proteins called claudins can be used to determine the differentiation of gastric mucosa. We investigated the expression of claudins in gastric cancer and proposed a new claudin‐based gastric cancer classification system. The expression of gastric (claudin‐18) and intestinal (claudin‐3 and claudin‐4) claudins in non‐neoplastic gastric mucosa (with intestinal metatplasia [IM], 78 cases; without IM, 88 cases) and 94 gastric cancers was analyzed immunohistochemically, as was the expression of gastric (MUC5A and MUC6) and intestinal (CD10 and MUC2) mucins. Heterogeneous expression of claudin‐3, claudin‐4 and claudin‐18 was detected in advanced gastric cancer; however, there was no significant association between the claudins and the clinicopathological parameters. These gastric cancer tissues were also subclassified into claudin‐based phenotypes: gastric claudin (G‐CLDN), 28 cases (30%); intestinal claudin (I‐CLDN), 41 cases (44%); and unclassified claudin (U‐CLDN), 25 cases (26%). Interestingly, the U‐CLDN gastric cancers had worse malignancy grades, not only in size and invasiveness but also in potential metastatic ability and patient outcome. Although the mucin‐based gastric cancer classification was also assessed, no significant correlation was found between mucin production and clinicopathological parameters. These observations suggest that loss of claudin expression may enhance the grade of malignancy of gastric cancer in vivo. Classification of gastric cancers using gastric and intestinal claudins is a good biomarker for assessing the risk of poor prognosis. (Cancer Sci 2007; 98: 1014–1019)

Cdx2 transcription factor regulates claudin‐3 and claudin‐4 expression during intestinal differentiation of gastric carcinoma

According to the expression of gastric (claudin‐18) and intestinal claudins (claudin‐3 and claudin‐4), the authors have previously proposed a new phenotypic classification of gastric carcinoma (GC): the gastric (G‐CLDN), intestinal (I‐CLDN) and unclassified claudin (U‐CLDN) phenotypes. The aim of the present study was to examine the role of Cdx2, the caudal‐related transcription factor, on the regulation of intestinal claudins expression in vitro and in vivo. It was confirmed on immunohistochemistry that non‐neoplastic gastric mucosa with intestinal metaplasia (IM) expressed Cdx2 with increased levels of intestinal claudin expression. In addition, Cdx2 expression was detected in 28 (30%) of 94 GC at the invasive front. Interestingly, Cdx2 expression had a significant association with the I‐CLDN phenotype (P < 0.001), which was almost identical to the established gastric and intestinal mucin‐based GC classification. Furthermore, the transfection of a recombinant human CDX2‐expressing vector into TMK‐1 (Cdx2‐negative) GC cells specifically elevated the expression of claudin‐3 and claudin‐4 at the mRNA (CLDN3, 3.9‐fold; CLDN4, 2.8‐fold) and protein levels (claudin‐3, 8.6‐fold; claudin‐4, 9.8‐fold), whereas no induction of the other claudins was detected. These findings suggest that Cdx2 plays an important role in the regulation of intestinal claudin expression not only in gastric mucosa with IM but also GC.

Significance of Akt Phosphorylation on Tumor Growth and Vascular Endothelial Growth Factor Expression in Human Gastric Carcinoma

Objective: Hypoxia is known to be a prevalent stress stimulus and increases the transcription of vascular endothelial growth factor (VEGF) mediated by hypoxia inducible factor-1α (HIF-1α). We investigated the role of phosphatidyl inositol-3 OH kinase (PI3K)-Akt signaling in the regulation of HIF-1α and VEGF expression in human gastric adenocarcinoma. Methods: The growth-inhibitory and apoptosis-inducing effects of the LY294002 PI3K inhibitor were analyzed in four gastric cancer cell lines and in vivo. The regulatory mechanism of VEGF and HIF-1α expression under hypoxic conditions was examined in the cell cultures. In 88 gastric cancer tissue samples, phosphorylated Akt and VEGF expression were analyzed immunohistochemically. Results: LY294002 suppressed cell proliferation but induced apoptosis with decreased levels of phosphorylated Akt. HIF-1α expression and VEGF secretion were induced under hypoxic conditions and VEGF protein secretion was significantly decreased by treatment with LY294002. In tumor samples, phosphorylated Akt expression was detected in 57% of the tumors, which was correlated with high VEGF expression, angiogenesis, clinicopathological parameters as well as a poor outcome. Conclusions: These findings suggest that phosphorylated Akt (Ser473) reflects the grade of malignancy in human gastric adenocarcinomas, not only in terms of tumor growth but also with respect to tumor angiogenesis.

Laparoscopic complete mesocolic excision for right-sided colon cancer using a cranial approach: anatomical and embryological consideration

BackgroundComplete mesocolic excision (CME) with central vascular ligation (CVL) should be employed for the treatment of colon cancer patients because of its superior oncological outcomes. However, this technique is technically challenging in laparoscopic right hemicolectomy because of the anatomical complexity of the transverse mesocolon.MethodsWe focused on the embryology and anatomy of the transverse mesocolon to overcome the difficulty of this surgery. The validity and efficacy of a cranial approach in achieving CME with CVL in laparoscopic right hemicolectomy was elucidated from the embryological point of view.ResultsIn total, 28 consecutive patients with right-sided colon cancer were treated by laparoscopic right hemicolectomy using a cranial approach. There were no conversion to open surgery or switching to another approach. Using this approach, torsion and fusion of the transverse mesocolon, which occurred during embryological development, could be reversed and the complex anatomy of the transverse mesocolon could be simplified before performing CVL of colonic vessels.ConclusionsA cranial approach is considered valid and useful for CME with CVL in laparoscopic right hemicolectomy from the embryological point of view.

The learning effect of using stereoscopic vision in the early phase of laparoscopic surgical training for novices

BackgroundRecently to improve depth perception, the performance of three-dimensional (3D) laparoscopic surgeries has increased. However, the effects of laparoscopic training using 3D are still unclear. This study aimed to clarify the effects of using a 3D monitor among novices in the early phase of training.MethodsParticipants were 40 novices who had never performed laparoscopic surgery (20 medical students and 20 junior residents). Three laparoscopic phantom tasks (task 1: touching markers on a flat disk with a rod; task 2: straight rod transfer through a single loop; and task 3: curved rod transfer through two loops) in the training box were performed ten times, respectively. Performances were recorded by an optical position tracker. The participants were randomly divided into two groups: one group performed each task five times initially under a 2D system (2D start group), and the other group performed each task five times under a 3D system (3D start group). Both groups then performed the same task five times. After the trial, we evaluated the performance scores (operative time, path length of forceps, and technical errors) and the learning curves for both groups.ResultsScores for all tasks performed under the 3D system were significantly better than scores for tasks using the 2D system. Scores for each task in the 2D start group improved after switching to the 3D system. However, scores for each task in the 3D start group were worse after switching to the 2D system, especially scores related to technical errors.ConclusionsThe stereoscopic vision improved laparoscopic surgical techniques of novices from the early phase of training. However, the performance of novices trained only by 3D worsened by changing to the 2D environment.

Outcomes and prognostic factors of selective lateral pelvic lymph node dissection with preoperative chemoradiotherapy for locally advanced rectal cancer

PurposeThe clinical significance of preoperative chemoradiotherapy (CRT) and lateral lymph node dissection (LLND) for locally advanced rectal cancer remains unclear. We have employed total mesorectal excision and selective LLND following preoperative CRT for patients with locally advanced rectal cancer. The validity of our strategy was evaluated.MethodsA total of 45 patients with locally advanced rectal cancer who underwent curative surgery after CRT from November 2005 to September 2016 were retrospectively analyzed. LLND was performed only for the patients with lateral lymph nodes suspected to have metastasis based on the pretreatment images.ResultsRates of 5-year overall survival (OS) and 5-year relapse-free survival (RFS) were 85.7 and 61.8%, respectively. Univariate and multivariate analyses detected only histological response (grades 2 and 3 vs. grade 1) as a significant prognostic factor for OS and local recurrence. ypN and ypStage were significant factors for RFS by univariate analysis, while no significant factor was detected by multivariate analysis. There was no significant factor for distant recurrence. In good responders (grades 2 and 3), the local recurrence rate was 0% (P = 0.006, vs. grade 1), while distant recurrence developed in 4 of 20 cases (20%, P = 0.615, vs. grade 1). There was no local recurrence in LLND (−) group regardless the histological response.ConclusionsAlthough selective LLND with preoperative CRT seems effective and valid for good responders, new treatment strategy is necessary for poor responders. Therefore, development of reliable biomarkers for histological response to CRT is an urgent need.

The effect on surgical skills of expert surgeons using 3D/HD and 2D/4K resolution monitors in laparoscopic phantom tasks

BackgroundRecently, several new imaging technologies, such as three-dimensional (3D)/high-definition (HD) stereovision and high-resolution two-dimensional (2D)/4K monitors, have been introduced in laparoscopic surgery. However, it is still unclear whether these technologies actually improve surgical performance.MethodsParticipants were 11 expert laparoscopic surgeons. We designed three laparoscopic suturing tasks (task 1: simple suturing, task 2: knotting thread in a small box, and task 3: suturing in a narrow space) in training boxes. Performances were recorded by an optical position tracker. All participants first performed each task five times consecutively using a conventional 2D/HD monitor. Then they were randomly divided into two groups: six participants performed the tasks using 3D/HD before using 2D/4K; the other five participants performed the tasks using a 2D/4K monitor before the 3D/HD monitor. After the trials, we evaluated the performance scores (operative time, path length of forceps, and technical errors) and compared performance scores across all monitors.ResultsSurgical performances of participants were ranked in decreasing order: 3D/HD, 2D/4K, and 2D/HD using the total scores for each task. In task 1 (simple suturing), some surgical performances using 3D/HD were significantly better than those using 2D/4K (P = 0.017, P = 0.033, P = 0.492 for operative time, path length, and technical errors, respectively). On the other hand, with operation in narrow spaces such as in tasks 2 and 3, performances using 2D/4K were not inferior to 3D/HD performances. The high-resolution images from the 2D/4K monitor may enhance depth perception in narrow spaces and may complement stereoscopic vision almost as well as using 3D/HD.ConclusionsCompared to a 2D/HD monitor, a 3D/HD monitor improved the laparoscopic surgical technique of expert surgeons more than a 2D/4K monitor. However, the advantage of 2D/4K high-resolution images may be comparable to a 3D/HD monitor especially in narrow spaces.

Recent updates in perioperative chemotherapy and recurrence pattern of gastric cancer

Gastrectomy with D2 lymph node dissection has become the global standard procedure for locally advanced gastric cancer to maximally reduce locoregional recurrence. In East Asia, based on the evidence of the ACTS‐GC and the CLASSIC trials, postadjuvant chemotherapy with S‐1 monotherapy or capecitabine and oxaliplatin after curative D2 gastrectomy is the current standard strategy. However, approximately 20% to 30% of patients still develop distant recurrence even after these postadjuvant chemotherapies, especially in those with pathological stage III disease. This review summarizes recent (2008‐2018) evidence on the benefits of adjuvant therapy for locally advanced gastric cancer. JACRO GC‐07, a Phase III trial, recently showed a superior 3‐year recurrence‐free survival of the S‐1 plus docetaxel regimen in comparison to S‐1 monotherapy for patients with pathological stage III gastric cancer after curative D2 gastrectomy. With regard to recent new evidence on neoadjuvant strategy, JCOG0501, a Phase III trial, did not show any superiority in 3‐year overall survival (OS) of additional neoadjuvant chemotherapy with S‐1/cisplatin over postadjuvant S‐1 monotherapy in scirrhous type gastric cancer. Further clinical trials of neoadjuvant chemotherapy are ongoing to improve the poor prognosis for gastric cancer with extensive lymph node metastases. These trials could lead to new evidence for improved treatment of gastric cancer in the near future.

Safe management of laparoscopic endoscopic cooperative surgery for superficial non-ampullary duodenal epithelial tumors

Background and study aims  Endoscopic submucosal dissection (ESD) for duodenal tumors results in a high delayed perforation rate due to the thinness of the duodenal wall. In most cases with perforation after duodenal ESD, additional surgery is needed due to severe peritonitis. A newly developed procedure, laparoscopic endoscopic cooperative surgery for duodenal tumors (D-LECS), may help to avoid perforation after ESD. In our institution, patients with superficial non-ampullary duodenal epithelial tumors (SNADET) smaller than 50 mm which could not have en-bloc resection by endoscopic mucosal resection were treated with D-LECS. After a laparoscopic exposure of anterior duodenal wall of second portion, ESD was performed. Laparoscopic suturing from the serosal side of ESD site was performed for reinforcement. There were neither postoperative leakage nor other complications. Therefore, D-LECS can be performed safely and prevent perforation after ESD for SNADET. D-LECS could be selected as a treatment for SNADET which can be cured by ESD.

Optimal Surgery for Mid-Transverse Colon Cancer: Laparoscopic Extended Right Hemicolectomy Versus Laparoscopic Transverse Colectomy

BackgroundAlthough the feasibility and safety of laparoscopic surgery for transverse colon cancer have been shown by the recent studies, the optimal laparoscopic approach for mid-transverse colon cancer is controversial.MethodsWe retrospectively analyzed the data of patients with the mid-transverse colon cancer at our institutions between January 2007 and April 2017. Thirty-eight and 34 patients who received extended right hemicolectomy and transverse colectomy, respectively, were enrolled.ResultsThere were no significant differences in operating time, blood loss, and hospital stay between the two groups. Postoperative complications developed in 10 of 34 patients (29.4%; wound infection: 2 cases, anastomotic leakage: 2 cases, bowel obstruction: 1 case, incisional hernia: 2 cases, others: 3 cases) for the transverse colectomy group and in 4 of 38 patients (10.5%; wound infection: 1 case, anastomotic leakage: 0 case, bowel obstruction: 2 cases, incisional hernia: 0 case, others: 1 case) for the extended right hemicolectomy group (P = 0.014). Although the median number of harvested #221 and #222 LNs was similar between the two groups (6 vs. 8, P = 0.710, and 3 vs. 2, P = 0.256, respectively), that of #223 was significantly larger in extended right hemicolectomy than in transverse colectomy (3 vs. 1, P = 0.038). The 5-year disease-free and overall survival rates were 92.4 and 90.3% for the extended right hemicolectomy group, and 95.7 and 79.6% for the transverse colectomy group (P = 0.593 and P = 0.638, respectively).ConclusionsLaparoscopic extended right hemicolectomy and laparoscopic transverse colectomy offer similar oncological outcomes for mid-transverse colon cancer. Laparoscopic extended right hemicolectomy might be associated with fewer postoperative complications.